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Effective problem solving, sound decision making, insightful invention—do such aspects of good thinking depend more on deep expertise in a specialty than on reflective awareness and general strategies? Over the past thirty years, considerable research and controversy have surrounded this issue. An historical sketch of the arguments for the strong specialist position and the strong generalist position suggests that each camp, in its own way, has oversimplified the interaction between general strategic knowledge and specialized domain knowledge. We suggest a synthesis: General and specialized knowledge function in close partnership. We explore the nature of this partnership and consider its implications for educational practice. [ABSTRACT FROM PUBLISHER]

Background: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients., Methods: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20)., Findings: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10 -5 , HR = 0.005 [95% CI: 0-0.31])., Interpretation: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology., Funding: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd., Competing Interests: Declaration of interests WEB—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences, named on a Kinomica patent; LN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; SFP—is an employee at Kinomica, owns Kinomica share options; AEC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; NN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JAC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; DNP—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; PMC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JK—is an employee at Kinomica, owns Kinomica share options; HRF—no conflict of interest; BP—no conflict of interest; PG—no conflict of interest; AA—no conflict of interest; AJA—received a honorarium for speaking engagements from Astellas; AT—received consultant fees from Kinomica for the role of Programme Director; AW—owns Kinomica share options, funded attendance and travel to conferences; GG—no conflict of interest; MDM—no conflict of interest; JGG—Kinomica co-founder, owns Kinomica share options; DJB—co-founder of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; PRC—co-founder and director of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; ADD—is an employee at Kinomica (CTO), named on Kinomica patents, Kinomica funded attendance and travel to conferences owns Kinomica share options., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Waste from end-of-life electrical and electronic equipment, known as e-waste, is a rapidly growing global problem. E-waste contains valuable materials that have an economic value when recycled. Unfortunately, the majority of e-waste is recycled in the unregulated informal sector and results in significant risk for toxic exposures to the recyclers, who are frequently women and children., Objectives: The aim of this study was to document the extent of the problems associated with inappropriate e-waste recycling practices., Methods: This was a narrative review that highlighted where e-waste is generated, where it is recycled, the range of adverse environmental exposures, the range of adverse health consequences, and the policy frameworks that are intended to protect vulnerable populations from inappropriate e-waste recycling practices., Findings: The amount of e-waste being generated is increasing rapidly and is compounded by both illegal exportation and inappropriate donation of electronic equipment, especially computers, from developed to developing countries. As little as 25% of e-waste is recycled in formal recycling centers with adequate worker protection. The health consequences of both direct exposures during recycling and indirect exposures through environmental contamination are potentially severe but poorly studied. Policy frameworks aimed at protecting vulnerable populations exist but are not effectively applied., Conclusions: E-waste recycling is necessary but it should be conducted in a safe and standardized manor. The acceptable risk thresholds for hazardous, secondary e-waste substances should not be different for developing and developed countries. However, the acceptable thresholds should be different for children and adults given the physical differences and pronounced vulnerabilities of children. Improving occupational conditions for all e-waste workers and striving for the eradication of child labor is non-negotiable., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Intensive (longer and more frequent) hemodialysis has emerged as an alternative to conventional hemodialysis for the treatment of patients with end-stage renal disease. However, given the differences in dialysis delivery and models of care associated with intensive dialysis, alternative approaches to patient management may be required. The purpose of this work was to develop a clinical practice guideline for the Canadian Society of Nephrology. We applied the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for guideline development and performed targeted systematic reviews and meta-analysis (when appropriate) to address prioritized clinical management questions. We included studies addressing the treatment of patients with end-stage renal disease with short daily (≥5 days per week, <3 hours per session), long (3-4 days per week, ≥5.5 hours per session), or long-frequent (≥5 days per week, ≥5.5 hours per session) hemodialysis. We included clinical trials and observational studies with or without a control arm (1990 and later). Based on a prioritization exercise, 6 interventions of interest included optimal vascular access type, buttonhole cannulation, antimicrobial prophylaxis for buttonhole cannulation, closed connector devices, and dialysate calcium and dialysate phosphate additives for patients receiving intensive hemodialysis. We developed 6 recommendations addressing the interventions of interest. Overall quality of the evidence was very low and all recommendations were conditional. We provide detailed commentaries to guide in shared decision making. The main limitation was the very low overall quality of evidence that precluded strong recommendations. Most included studies were small single-arm observational studies. Three randomized controlled trials were applicable, but provided only indirect evidence. Published information for patient values and preference was lacking. In conclusion, we provide 6 recommendations for the practice of intensive hemodialysis. However, due to very low-quality evidence, all recommendations were conditional. We therefore also highlight priorities for future research., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients treated with conventional hemodialysis (HD) develop disorders of mineral metabolism that are associated with increased morbidity and mortality. More frequent and longer HD has been associated with improvement in hyperphosphatemia that may improve outcomes., Study Design: Systematic review and meta-analysis to inform the clinical practice guideline on intensive dialysis for the Canadian Society of Nephrology., Setting & Population: Adult patients receiving outpatient long (≥5.5 hours/session; 3-4 times per week) or long-frequent (≥5.5 hours/session, ≥5 sessions per week) HD., Selection Criteria for Studies: We included clinical trials, cohort studies, case series, case reports, and systematic reviews., Interventions: Dialysate calcium concentration ≥1.5 mmol/L and/or phosphate additive., Outcomes: Fragility fracture, peripheral arterial and coronary artery disease, calcific uremic arteriolopathy, mortality, intradialytic hypotension, parathyroidectomy, extraosseous calcification, markers of mineral metabolism, diet liberalization, phosphate-binder use, and muscle mass., Results: 21 studies were identified: 2 randomized controlled trials, 2 reanalyses of data from the randomized controlled trials, and 17 observational studies. Dialysate calcium concentration ≥1.5 mmol/L for patients treated with long and long-frequent HD prevents an increase in parathyroid hormone levels and a decline in bone mineral density without causing harm. Both long and long-frequent HD were associated with a reduction in serum phosphate level of 0.42-0.45 mmol/L and a reduction in phosphate-binder use. There was no direct evidence to support the use of a dialysate phosphate additive., Limitations: Almost all the available information is related to changes in laboratory values and surrogate outcomes., Conclusions: Dialysate calcium concentration ≥1.5 mmol/L for most patients treated with long and long-frequent dialysis prevents an increase in parathyroid hormone levels and decline in bone mineral density without increased risk of calcification. It seems prudent to add phosphate to the dialysate for patients with a low predialysis phosphate level or very low postdialysis phosphate level until more evidence becomes available., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Practices in vascular access management with intensive hemodialysis may differ from those used in conventional hemodialysis., Study Design: We conducted a systematic review to inform clinical practice guidelines for the provision of intensive hemodialysis., Setting & Population: Adult patients receiving maintenance (>3 months) intensive hemodialysis (frequent [≥5 hemodialysis treatments per week] and/or long [>5.5 hours per hemodialysis treatment])., Selection Criteria for Studies: We searched EMBASE and MEDLINE (1990-2011) for randomized and observational studies. We also searched conference proceedings (2007-2011)., Interventions: (1) Central venous catheter (CVC) versus arteriovenous (AV) access, (2) buttonhole versus rope-ladder cannulation, (3) topical antimicrobial cream versus none in buttonhole cannulation, and (4) closed connector devices among CVC users., Outcomes: Access-related infection, survival, hospitalization, patency, access survival, intervention rates, and quality of life., Results: We included 23, 7, and 5 reports describing effectiveness by access type, buttonhole cannulation, and closed connector device, respectively. No study directly compared CVC with AV access. On average, bacteremia and local infection rates were higher with CVC compared with AV access. Access intervention rates were higher with more frequent hemodialysis, but access survival did not differ. Buttonhole cannulation was associated with bacteremia rates similar to those seen with CVCs in some series. Topical mupirocin seemed to attenuate this effect. No direct comparisons of closed connector devices versus standard luer-locking devices were found. Low rates of actual or averted (near misses) air embolism and bleeding were reported with closed connector devices., Limitations: Overall, evidence quality was very low. Limited direct comparisons addressing main review questions, small sample sizes, selective outcome reporting, publication bias, and residual confounding were major factors., Conclusions: This review highlights several differences in the management of vascular access in conventional and intensive hemodialysis populations. We identify a need for standardization of vascular access outcome reporting and a number of priorities for future research., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The need to find biomarkers for hepatobiliary diseases including cholangiocarcinoma (CCA) has led to an interest in using bile as a proximal fluid in biomarker discovery experiments, although there are inherent challenges both in its acquisition and analysis. The study described here greatly extends previous studies that have started to characterise the bile proteome. Bile from four patients with hilar CCA was depleted of albumin and immunoglobulin G and analysed by GeLC-MS/MS. The number of proteins identified per bile sample was between 378 and 741. Overall, the products of 813 unique genes were identified, considerably extending current knowledge of the malignant bile proteome. Of these, 268 were present in at least 3 out of 4 patients. This data set represents the largest catalogue of bile proteins to date and together with other studies in the literature constitutes an important prelude to the potential promise of expression proteomics and subsequent validation studies in CCA biomarker discovery., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Because mercury contamination is potentially threatening to bald eagle (Haliaeetus leucocephalus) populations, we collected molted feathers at nests to determine the level of contamination in bald eagles in the state of Idaho, USA. Eagle feathers contained measurable amounts of cadmium (Cd), chromium (Cr), selenium (Se), lead (Pb), as well as mercury (Hg). Cadmium, Cr, Se, and Pb levels averaged 0.17, 4.68, 2.02, and 1.29 mg/kg dry weight, respectively, and were at or below concentrations indicated as causing reproductive failure in bald eagles. Mercury contamination was found to be the highest averaging 18.74 mg/kg dry weight. Although a concentration of only 7.5 mg/kg dry weight Hg in bird feathers can cause reduced productivity and even sterility, all of the eagles we sampled bred successfully and the population of bald eagles continues to grow annually throughout the state.

During the initial phases of a study focussed on discovering new urinary biomarkers for renal cell carcinoma, a number of challenges and limitations were identified, which we subsequently investigated. The purpose of this report is to provide insight into experimental design for such investigations and potential confounding factors that can impact on such studies. Sixty urine samples from 20 patients with clear cell renal cell carcinoma and ten live renal transplant donor patients, pre- and post-nephrectomy, were profiled using SELDI-TOF-MS incorporating stringent quality control and in-house data processing/analysis. There were 65 significantly differentially expressed peaks (five solitary peaks and four peak clusters that increased post nephrectomy and four peak clusters that decreased). Peak 3934 Da m/z and peaks within 11731-11961 Da m/z, which increased post nephrectomy were identified as the 36 amino acid isoform of β-defensin-1 and β(2) -microglobulin, respectively. However, changes in these two protein forms were also seen in healthy donors following nephrectomy implying a relationship with kidney removal per se rather than tumour removal. This study indicates the difficulties in identifying SELDI peaks for subsequent validation and illustrates the need for appropriate controls in biomarker studies to determine whether changes are indirect consequences of treatment., (Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Proteomic profiling using mass spectrometry (MS) is one of the most promising methods for the analysis of complex biological samples such as urine, serum and tissue for biomarker discovery. Such experiments are often conducted using MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) and SELDI-TOF (surface-enhanced laser desorption/ionisation time-of-flight) MS. Using such profiling methods it is possible to identify changes in protein expression that differentiate disease states and individual proteins or patterns that may be useful as potential biomarkers. However, the incorporation of quality control (QC) processes that allow the identification of low quality spectra reliably and hence allow the removal of such data before further analysis is often overlooked. In this paper we describe rigorous methods for the assessment of quality of spectral data. These procedures are presented in a user-friendly, web-based program. The data obtained post-QC is then examined using variance components analysis to quantify the amount of variance due to some of the factors in the experimental design., Results: Using data from a SELDI profiling study of serum from patients with different levels of renal function, we show how the algorithms described in this paper may be used to detect systematic variability within and between sample replicates, pooled samples and SELDI chips and spots. Manual inspection of those spectral data that were identified as being of poor quality confirmed the efficacy of the algorithms. Variance components analysis demonstrated the relatively small amount of technical variance attributable to day of profile generation and experimental array., Conclusion: Using the techniques described in this paper it is possible to reliably detect poor quality data within proteomic profiling experiments undertaken by MS. The removal of these spectra at the initial stages of the analysis substantially improves the confidence of putative biomarker identification and allows inter-experimental comparisons to be carried out with greater confidence.

Normalisation of data to minimise the impact of technical variation on comparative sample analysis is often carried out. Using SELDI data as a model, we have examined the effects of normalisation by TIC which is commonly used for MS data. Significant intergroup differences in normalisation factor were found for serum profiles which could not be explained by experimental factors, implying that normalisation by TIC may in some situations also normalise biological differences and should be systematically evaluated.

A database of 5448 peptide tandem mass spectra acquired in a quadrupole time-of-flight mass spectrometer was generated for peptides derived from proteins digested with trypsin. Peptides were identified from their mass spectra by the Mascot algorithm. Statistical models were then used to investigate factors influencing the abundance of ions formed. Separate models were formulated for b and y ions as it was thought that different factors may influence the formation of each type of ion. Several factors were found to have a highly significant influence on the abundance of ions formed. These include the actual mass of the ion formed after fragmentation as well as the location of the cleavage. The composition of the fragmenting peptide was also found to be important, and amino acids either side of the fragmentation site influenced the abundance of ions produced. To increase understanding of fragmentation mechanisms, the effect of several physicochemical properties of these residues was also investigated in a separate model. In conclusion, the models formulated for b and y ions provide useful characterization of the abundance of ions formed, and this information could be used to develop improved algorithms for peptide identification.

Several algorithms have been described in the literature for protein identification by searching a sequence database using mass spectrometry data. In some approaches, the experimental data are peptide molecular weights from the digestion of a protein by an enzyme. Other approaches use tandem mass spectrometry (MS/MS) data from one or more peptides. Still others combine mass data with amino acid sequence data. We present results from a new computer program, Mascot, which integrates all three types of search. The scoring algorithm is probability based, which has a number of advantages: (i) A simple rule can be used to judge whether a result is significant or not. This is particularly useful in guarding against false positives. (ii) Scores can be compared with those from other types of search, such as sequence homology. (iii) Search parameters can be readily optimised by iteration. The strengths and limitations of probability-based scoring are discussed, particularly in the context of high throughput, fully automated protein identification.

The PROMISE (Prosthetic centres andmetalions in protein activesites) database aims to gather together comprehensive sequence, structural, functional and bibliographic information on proteins which possess prosthetic centres, with an emphasis on active site structure and function. The database is available on the World Wide Web at http://bioinf.leeds.ac.uk/promise/

PRINTS is a compendium of protein motif fingerprints derived from the OWL composite sequence database. Fingerprints are groups of motifs within sequence alignments whose conserved nature allows them to be used as signatures of family membership. Fingerprints inherently offer improved diagnostic reliability over single motif methods by virtue of the mutual context provided by motif neighbors. To date, 650 fingerprints have been constructed and stored in PRINTS, the size of which has doubled in the last 2 years. The current version, 14.0, encodes 3500 motifs, covering a range of globular and membrane proteins, modular polypeptides, and so on. The database is now accessible via the UCL Bioinformatics Server on http:@ www.biochem.ucl.ac.uk/bsm/dbbrowser/. We describe here progress with the database, its compilation and interrogation software, and its Web interface.

A tool for searching pattern and fingerprint databases is described. Fingerprints are groups of motifs excised from conserved regions of sequence alignments and used for iterative database scanning. The constituent motifs are thus encoded as small alignments in which sequence information is maximised with each database pass; they therefore differ from regular-expression patterns, in which alignments are reduced to single consensus sequences. Different database formats have evolved to store these disparate types of information, namely the PROSITE dictionary of patterns and the PRINTS fingerprint database, but programs have not been available with the flexibility to search them both. We have developed a facility to do this: the system allows query sequences to be scanned against either PROSITE, the full PRINTS database, or against individual fingerprints. The results of fingerprint searches are displayed simultaneously in both text and graphical windows to render them more tangible to the user. Where structural coordinates are available, identified motifs may be visualised in a 3D context. The program runs on Silicon Graphics machines using GL graphics libraries and on machines with X servers supporting the PEX extension: its use is illustrated here by depicting the location of low-density lipoprotein-binding (LDL) motifs and leucine-rich repeats in a mosaic G-protein-coupled receptor (GPCR).

VISTAS is a suite of programs for protein sequence and structure analysis. The system allows the simultaneous display, in separate windows, of multiple sequence alignments, of known or model 3D structures, and of 2D graphic representations of sequence and/or alignment properties. The displays are fully integrated, and therefore manipulations in one window can be reflected in each of the others. Beyond its display facilities, VISTAS brings together a number of existing tools under a single, user-friendly umbrella: these include a fully functional interactive color alignment procedure, conserved motif selection, a range of database-scanning routines, and interactive access to the OWL composite sequence database and to the PRINTS protein fingerprint database. Exploration of the sequence database is thus straightforward, and predefined structural motifs from the fingerprint database may be readily visualized. Of particular note is the ability to calculate conservation criteria from sequence alignments and to display the information in a 3D context: this renders VISTAS a powerful tool for aiding mutagenesis studies and for facilitating refinement of molecular models.

It has been suggested that a perceived rhythmic organization may mediate remembering musical and other stimuli. This experiment examined whether or not Ss could register and remember position in a sequence using rhythmic grouping. Sixteen Ss heard tapped sequences 24-63 beats long, accented to encourage grouping by 4s. Ss tapped responses revealing whether or not they remembered the sequence length-the last tap's position. Significantly more incorrect responses were off by multiples of 4 beats than by adjacent amounts; these frequent errors of whole rhythmic groups of 4 showed that Ss coded sequence length rhythmically. Ss proved 53% accurate over four response conditions, with individual's scores ranging from 8% to 87%. It was concluded that Ss could count with rhythmic hierarchies, essentially equivalent to counting with a nonstandard number base, to code sequential position.

The ability to discriminate whether pictured box shapes (parallelopipeds) are projections of three-dimensional rectangular forms has been demonstrated by Perkins and Cooper in US populations and interpreted as a symptom of a general Gestalt strategy in perception. Deregowski suggested earlier that this perceptual strategy might not appear as strongly in less 'carpentered' cultures, among perceivers less familiar with Western modes of depiction. A study is reported in which the performance on the discrimination by US children in grades 1, 4, and 7; and children from Zimbabwe, Africa, in grades 1, 2, 4, and 7--children of less experience with pictures and urban environments--has been examined. All groups evinced the discrimination at high levels of statistical significance. However, the findings disclosed much less accurate performance in the Zimbabwe groups at all grade levels, and no improvement with age either in the US or in Zimbabwe. The absence of improvement argues against an explanation of the difference between the US and Zimbabwe groups in terms of either a carpentered-world hypothesis or a difficulty with picture perception, at least when those interpretations are taken in their simplest forms.

'Good form' theories of perception leave some latitude concerning how casually or cautiously order is imposed on the stimulus. Exploring this issue, the present experiment introduced a series of figures admitting up to three alternative 'good' readings. Eight college students estimated two angles in each of fifty-six pictured spatial forms. Theory predicted that geometrical regularities of rectangularity and symmetry would dominate their estimates. But a regularity would rarely appear when inconsistent with projective geometry and the given figure. The accuracy of subjects' estimates was also assessed. The results confirmed the hypotheses at high significance levels, arguing that such figures are interpreted through an order-imposing process restrained by projective geometry, and that subjects could make roughly accurate estimates based on the imposed order. Parallels with computer scene analysis are discussed. It is concluded that perceptual presumption of certain 'good forms' runs little risk of misinterpreting the stimulus.